Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer

Abstract

Targeting Hsp90 is an attractive strategy for anticancer therapy because the diversity and relevance of biological processes are regulated by these proteins in most cancers. However, the role and mode of action of Hsp90 inhibitors in pancreatic cancer has not been studied. This study aimed to assess the antitumor activity of the Hsp90 inhibitor, IPI-504, in pancreatic cancer and to determine the biological effects of the agent. In vitro, we show that pharmacologic inhibition of Hsp90 by IPI-504 exerts antiproliferative effects in a panel of pancreatic cancer cells in a dose-and time-dependent manner. In pancreatic cancer xenografts obtained directly from patients with pancreas cancer, the agent resulted in a marked suppression of tumor growth. Although known Hsp90 client proteins were significantly modulated in IPI-504-treated cell line, no consistent alteration of these proteins was observed in vivo other than induction of Hsp70 expression in the treated xenografted tumors. Using a proteomic profiling analysis with isotope tags for relative and absolute quantitation labeling technique, we have identified 20 down-regulated proteins and 42 up-regulated proteins on IPI-504 treatment.tumor growth Identical changes were observed in the expression of the genes coding for these proteins in a subset of proteins including HSPA1B, LGALS3, CALM1, FAM84B, FDPS, GOLPH2, HBA1, HIST1H1C, HLA-B, and MARCKS. The majority of these proteins belong to the functional class of intracellular signal transduction, immune response, cell growth and maintenance, transport, and metabolism. In summary, we show that IPI-504 has potent antitumor activity in pancreatic cancer and identify potential pharmacologic targets using a proteomics and gene expression profiling.

The expanding proteome of the molecular chaperone HSP90

“…Despite the large number of inhibitormodulated hits obtained by Sharma et al, surprisingly few of the proteins identified by previous proteomic surveys [25][26][27][28] were reproduced in this new study. Comparison of the proteins the levels of which were changed by more than 1.5-fold revealed that only 8 of the 23 detected by Maloney et al, 25 9 of the 97 found by Schumacher et al, 26 5 of the 34 from Song et al 27 and 3 of the 87 from Yao et al 28 were also present in the Sharma et al catalog.…”

“…Comparison of the proteins the levels of which were changed by more than 1.5-fold revealed that only 8 of the 23 detected by Maloney et al, 25 9 of the 97 found by Schumacher et al, 26 5 of the 34 from Song et al 27 and 3 of the 87 from Yao et al 28 were also present in the Sharma et al catalog. No proteins were common to more than 3 of the 5 studies.…”

“…Another LC-MS/MS study, this time using iTRAQ (isobaric tag for relative and absolute quantitation)-labeled peptides, tracked proteomic changes in two human pancreatic cancer cell lines treated with the more water-soluble geldanamycin analog IPI-504. 27 The investigators identified 20 downregulated and 42 upregulated proteins common to both cell lines. Analysis of these proteins in the human protein database revealed most downregulated proteins to be involved in macromolecule metabolism, cell localization, cell growth and maintenance and transport, whereas the upregulated proteins were mostly involved in cellular metabolism and cell organization and biogenesis.…”

The Hsp90 inhibitor IPI-504 rapidly lowers EML4–ALK levels and induces tumor regression in ALK-driven NSCLC models

“…The biological and anti-neoplastic effects of IPI-504 have been demonstrated in multiple in vitro and in vivo models of cancer (Bauer et al, 2006;Peng et al, 2007;Dewaele et al, 2008;Song et al, 2008;Leow et al, 2009) leading to its clinical development in various phase 2 studies (clinicaltrials.gov).…”

Molecular basis for the actions of Hsp90 inhibitors and cancer therapy

“…IPI-504 has been found to display antitumor activity against pancreatic cancer xenografts and is a promising compound against gastrointestinal stromal tumors of platelet-derived growth factor receptor-a mutants. 50 Genistein, an isoflavone, inhibits EGFR tyrosine kinase, 51 and also inhibits the Hsp90 deacetylase (HDAC6)-Hsp90 co-chaperone function, which downregulates the expression of androgen receptor in androgen-dependent prostate cancer cell lines. 52 Quercetin, a flavonoid, inhibits cancer cells that over-express ErbB2 (Her-2/neu) trans-membrane tyrosine kinase and downregulates the downstream PI3K-Akt signaling pathway.…”